Clinical Implications of Low Cell‐Free DNA Fetal Fraction in Non‐Invasive Prenatal Testing: A Retrospective Cohort Study of 40,716 Pregnancies

OBJECTIVE: This study aimed to investigate the association between fetal fraction (FF) on non-invasive prenatal testing (NIPT) and pregnancy-related complications using a large sample to support improved prenatal management. METHODS: This retrospective cohort study included women with singleton pregnancies and negative NIPT results between January 2015 and March 2022 as part of the Japan Multicenter Study. Chi-square tests and binary logistic regression analyses were used to assess the association between FF and pregnancy-related complications. RESULTS: (1) = 2.84, p = 0.09). Women in the low FF group (FF < 10.27%, < 25th percentile) had higher risks of fetal demise, adjusted OR = 1.79, 95% CI [1.31, 2.43]), preterm birth (adjusted OR = 1.63, 95% CI [1.30, 2.06]), fetal growth restriction (FGR) (adjusted OR = 1.50, 95% CI [1.10, 2.05]), and hypertensive disorders of pregnancy (HDP) (adjusted OR = 1.44, 95% CI [1.24, 1.66]). No significant differences were observed for gestational diabetes mellitus (GDM) (adjusted OR = 1.13, 95% CI [0.99, 1.30], p = 0.081). CONCLUSION: Low FF on NIPT is associated with an increased risk of several pregnancy complications, highlighting the need for careful management.